Topoisomerase I-mediated DNA cleavage as a guide to the development of antitumor agents derived from the marine alkaloid lamellarin D: triester derivatives incorporating amino acid residues

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…Selected structures of lamellarins isolated from ascidians Following the discovery of the potent anti-proliferative and proapoptotic activities of lamellarins, their biological activities have been extensively studied, in particular their capacities to interfere with topoisomerase (TOPO) I and mitochondria, both contributing to their potent cytotoxicity. Although all the aspects of the lamellarins' mechanism of action are not completely known, it has been demonstrated that they are potent inhibitors of topoisomerase (TOPO) I, they interact with DNA, they target mitochondria directly, and they induce the release of cytochrome C and apoptosis-inducing factor (AIF) [51,[53][54][55][56][57][58]. Lamellarin D (81) was identified as a potent TOPO I poison in 2003 [53]; it binds relatively weakly to DNA, presumably via the insertion of its planar pentacyclic chromophore between DNA base pairs.…”

“…Lamellarin D (81) was identified as a potent TOPO I poison in 2003 [53]; it binds relatively weakly to DNA, presumably via the insertion of its planar pentacyclic chromophore between DNA base pairs. Intercalation of the flat chromophore between two adjacent base pairs exposes the perpendicular methoxyphenol moiety toward the major groove of DNA where the enzyme can be trapped [54,55]. This DNA interaction, although relatively weak, provides the necessary anchorage for stabilization of the enzyme-DNA complex.…”

“…Another general observation is that the planarity of the pharmacophore conferred by the double bond between carbons 5 and 6 in the quinoline B-ring is a crucial element for cytotoxicity and TOPO I inhibition; when this double bond is lacking, as in lamellarin K (79), for example, the planar conformation no longer exists and the drug loses its capacity to interfere with TOPO I. This was clearly demonstrated using pairs of lamellarins, each of which contains exactly the same substituents and differs only in the nature of the C5/C6 bond, where the presence of the C5/C6 double bond significantly decreases the IC50 values [40,53,54,60].…”

“…However, it has been subsequently reported that all of the phenolic hydroxyl groups at each of the C8, C14, and C20 positions of lamellarin D are important for maintaining activity against TOPO I and potent cytotoxic action. It has been also found that these groups could be substituted with positively charged amino acid derivatives without loss of activity [54]. Furthermore, it has pointed out that almost any modifications of the substitution pattern on lamellarin D decrease the cytotoxicity of the molecule [38,60].…”

Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR

“…in 1985. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] These lamellarins exhibit a number of interesting biological activities such as potent cytotoxicity against cancer cell lines, 8,9,11,12,[14][15][16][17][18][19][20][21] multi-drug resistance (MDR) reversal activity, 15,16 anti-HIV activity, 11,18,22 topoisomerase I inhibitory activity, 23,24 inhibition of mitochondrial function, [25][26][27][28] and protein kinases inhibitory activity. 29 Lamellarins possess a unique 14-phenyl-6H- [1]benzopyrano- According to X-ray crystallographic analyses of several lamellarins, the aryl group attached to C1 is This paper is dedicated to Professor Dr. Victor Snieckus on the occasion of his 77 th birthday.…”